Cellular differentiation is a complex process for which the molecular mechanisms are poorly understood. Differentiation is frequently associated with an altered pattern of growth. One extreme example of the coupling of growth and differentiation is terminal differentiation,whereby, cells irreversibly lose proliferative capacity in addition to expressing new structural genes. How changes in growth potential are related to expression of the differentiated phenotype is at present unknown. In general, malignant cells which have lost growth control appear "frozen" in a particular state of differentiation. Some transformed cells can be induced to terminally differentiate in culture (and others fail to differentiate in response to appropriate signals). We have focused our attention on questions related to the role of the c-myc oncogene in the differentiation process of murine erythroleukemia (MEL) and H630 colon carcinoma cells. Important break-troughs for the understanding of Myc function came with the discovery of Max, a co-factor for Myc's transcriptional activity. Through studies of stable MEL transfectants we were able to demonstrate that clones overexpressing Myc are blocked in their potential to differentiate. Conversely clones overexpressing wt-Max grow slowly, and are delayed in inducer-mediated differentiation while clones overexpressing basic region mutant(bm) max exhibit growth retardation, accelerated inducer-mediated differentiation, accumulation in the GO/G1 phase of the cell cycle and spontaneous differentiation. Mutant proteins, such as bm-Max which interfere with the formation of productive complexes, can disrupt Myc/Max function. This indicates that it may be possible to exploit obligate complex formation as a therapeutic target in the treatment of cancer. Therefore, we plan to use short synthetic peptides to block the formation of active transactivating Myc/Max complexes.